Abstract
Peroxisomes produce hydrogen peroxide as a metabolic by-product of their many oxidase enzymes, but contain catalase that breaks down hydrogen peroxide in order to maintain the organelle’s oxidative balance. It has been previously demonstrated that, as cells age, catalase is increasingly absent from the peroxisome, and resides instead as an unimported tetrameric molecule in the cell cytosol; an alteration that is coincident with increased cellular hydrogen peroxide levels. As this process begins in middle-passage cells, we sought to determine whether peroxisomal hydrogen peroxide could contribute to the oxidative damage observed in mitochondria in late-passage cells. Early-passage human fibroblasts (Hs27) treated with aminotriazole (3-AT), an irreversible catalase inhibitor, demonstrated decreased catalase activity, increased levels of cellular hydrogen peroxide, protein carbonyls, and peroxisomal numbers. This treatment increased mitochondrial reactive oxygen species levels, and decreased the mitochondrial aconitase activity by ∼85% within 24 h. In addition, mitochondria from 3-AT treated cells show a decrease in inner membrane potential. These results demonstrate that peroxisome-derived oxidative imbalance may rapidly impair mitochondrial function, and considering that peroxisomal oxidative imbalance begins to occur in middle-passage cells, supports the hypothesis that peroxisomal oxidant release occurs upstream of, and contributes to, the mitochondrial damage observed in aging cells.
Highlights
Peroxisomes are ubiquitous subcellular organelles present in almost all eukaryotic cells and house a wide variety of indispensable metabolic reactions, the majority of which produce hydrogen peroxide (H2O2) as by-product
INHIBITION OF PEROXISOMAL CATALASE 3-AT has previously been demonstrated to be an irreversible inhibitor of catalase from a number of eukaryotes
EFFECTS OF PEROXISOMAL CATALASE INHIBITION ON MITOCHONDRIAL FUNCTION We have previously demonstrated the age-dependent decrease in mitochondrial inner membrane potential in late-passage human fibroblasts, which could be restored to normal, early-passage levels by the introduction of catalase bearing the more efficient – SKL peroxisomal targeting signal (Koepke et al, 2008)
Summary
Peroxisomes are ubiquitous subcellular organelles present in almost all eukaryotic cells and house a wide variety of indispensable metabolic reactions, the majority of which produce hydrogen peroxide (H2O2) as by-product (reviewed by Schrader and Fahimi, 2006). Peroxisomes lack DNA and translational machinery and all peroxisomal membrane and matrix proteins are encoded by the nuclear genome, synthesized in the cytosol on free polyribosomes and imported post-translationally (reviewed by Lazarow and Fujiki, 1985). The progressive mislocalization of catalase has been demonstrated to occur in cells as early as middle-passage (PDL30-40) This leads to the disequilibrium between H2O2 producing and clearing reactions within the organelle, transitioning the peroxisome into a significant source of reactive oxygen species (ROS) and contributing to the elevated levels characteristic of late-passage cells and tissues (Terlecky et al, 2006)
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